We have continued our studies of the immunobiology of the Epstein-Barr virus in order to clarify the defense mechanisms which regulate the capacity of this potentially oncogenic virus to induce controlled B lymphocyte proliferation, differentiation for immunoglobulin secretion, and cellular transformation. In the past we have identified four distinct suppressor T cell immunoregulatory mechanisms which can affect EBV induced B cell differentiation and have characterized the cellular control processes which occur during acute infection (i.e. infectious mononucleosis) and in convalescent EBV immune normal subjects. We have extended these studies with the development of sensitive limiting dilution techniques for determining the frequency of EBV infected B lymphocytes present during acute infection (500-5000/10 to the 6 B cells) and after recovery (1-10/10 to the 6 B cells). Patients with rheumatoid arthritis were found to have a striking defect in their suppressor T cell response directed specifically at EBV and as a consequence have ten times the normal burden of EBV infected B cells in the circulation. Interestingly, although essentially all B lymphocytes have receptors for EBV, we found that only about 1% of these cells become activated to produce immunoglobulin after infection and only 0.3% of B cells will ultimately become transformed. We have studied 27 patients with the chronic infectious mononucleosis syndrome and have been able to group these patients with three subgroups based on their cellular response to EBV. In one of these patient groups, a unique antisuppressor T cell activity was found. Further, we have found that normal monocytes may also have anti or contrasuppressor activity for certain T cell functions in man. These observations help us to define yet another major immunoregulatory cell circuit in the human immune system in which defects may predispose or contribute to disease.